National Institute of Neuroscience Italy

Sant'Ambrogio di Torino, Italy

National Institute of Neuroscience Italy

Sant'Ambrogio di Torino, Italy
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Morello N.,University of Turin | Plicato O.,University of Turin | Piludu M.A.,University of Cagliari | Poddighe L.,University of Cagliari | And 6 more authors.
PLoS ONE | Year: 2017

Stressful events evoke molecular adaptations of neural circuits through chromatin remodeling and regulation of gene expression. However, the identity of the molecular pathways activated by stress in experimental models of depression is not fully understood. We investigated the effect of acute forced swimming (FS) on the phosphorylation of the extracellular signal-regulated kinase (ERK)1/2 (pERK) and histone H3 (pH3) in limbic brain areas of genetic models of vulnerability (RLA, Roman low-avoidance rats) and resistance (RHA, Roman high-avoidance rats) to stress-induced depression-like behavior. We demonstrate that FS markedly increased the density of pERK-positive neurons in the infralimbic (ILCx) and the prelimbic area (PrLCx) of the prefrontal cortex (PFCx), the nucleus accumbens, and the dorsal blade of the hippocampal dentate gyrus to the same extent in RLA and RHA rats. In addition, FS induced a significant increase in the intensity of pERK immunoreactivity (IR) in neurons of the PFCx in both rat lines. However, RHA rats showed stronger pERK-IR than RLA rats in the ILCx both under basal and stressed conditions. Moreover, the density of pH3-positive neurons was equally increased by FS in the PFCx of both rat lines. Interestingly, pH3-IR was higher in RHA than RLA rats in PrLCx and ILCx, either under basal conditions or upon FS. Finally, colocalization analysis showed that in the PFCx of both rat lines, almost all pERK-positive cells express pH3, whereas only 50% of the pH3-positive neurons is also pERK-positive. Moreover, FS increased the percentage of neurons that express exclusively pH3, but reduced the percentage of cells expressing exclusively pERK. These results suggest that (i) the distinctive patterns of FS-induced ERK and H3 phosphorylation in the PFCx of RHA and RLA rats may represent molecular signatures of the behavioural traits that distinguish the two lines and (ii) FS-induced H3 phosphorylation is, at least in part, ERK-independent. © 2017 Morello et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Ciccarelli A.,University of Turin | Giustetto M.,University of Turin | Giustetto M.,National Institute of Neuroscience Italy
Neuropharmacology | Year: 2014

It is well-established that neuronal intracellular signaling governed by the extracellular signal-regulated kinase (ERK/MAPK) plays a crucial role in long-term adaptive changes that occur during cognitive processes. ERK is a downstream component of a conserved signaling module that is activated by the serine/threonine kinase, Raf, which activates the MAPK/ERK kinase (MEK)1/2 protein kinases, which, in turn, activate ERK1/2. This signaling pathway has been reported to be activated in numerous physiological conditions due to a variety of stimuli, ranging from the activation of ionotropic glutamatergic receptors to metabotropic dopaminergic receptors and neurotrophin receptors. Interestingly, activated ERK can have early and late downstream effects at both the nuclear and synaptic levels. Locally, ERK signaling results in transient changes in the efficacy of synaptic transmission by modifying both pre- and post-synaptic targets. Once translocated into the nucleus, ERK signaling may control transcription by targeting several different regulators of gene expression such as transcription factors and histone proteins. ERK function is considered fundamental in processes such as long-term memory storage and drug addiction, by means of its role in activity-dependent epigenetic modifications that occur in the brain. In this review, we summarize the current understanding of ERK action in the neuroepigenetic processes underlying physiological responses, cognitive processes and drug addiction. This article is part of the Special Issue entitled 'Neuroepigenetic Disorders'. © 2014 Elsevier Ltd. All rights reserved.

Diano M.,University of Turin | Diano M.,Koelliker Hospital | D'Agata F.,University of Turin | Cauda F.,University of Turin | And 14 more authors.
Cerebellum | Year: 2016

The cerebellum has been traditionally considered a sensory-motor structure, but more recently has been related to other cognitive and affective functions. Previous research and meta-analytic studies suggested that it could be involved in pain processing. Our aim was to distinguish the functional networks subserved by the cerebellum during pain processing. We used functional magnetic resonance imaging (fMRI) on 12 subjects undergoing mechanical pain stimulation and resting state acquisition. For the analysis of data, we used fuzzy c-mean to cluster cerebellar activity of each participant during nociception. The mean time courses of the clusters were used as regressors in a general linear model (GLM) analysis to explore brain functional connectivity (FC) of the cerebellar clusters. We compared our results with the resting state FC of the same cluster and explored with meta-analysis the behavior profile of the FC networks. We identified three significant clusters: cluster V, involving the culmen and quadrangular lobules (vermis IV-V, hemispheres IV-V-VI); cluster VI, involving the posterior quadrangular lobule and superior semilunar lobule (hemisphere VI, crus 1, crus 2), and cluster VII, involving the inferior semilunar lobule (VIIb, crus1, crus 2). Cluster V was more connected during pain with sensory-motor areas, cluster VI with cognitive areas, and cluster VII with emotional areas. Our results indicate that during the application of mechanical punctate stimuli, the cerebellum is not only involved in sensory functions but also with areas typically associated with cognitive and affective functions. Cerebellum seems to be involved in various aspects of nociception, reflecting the multidimensionality of pain perception. © 2015, Springer Science+Business Media New York.

Tomassy G.S.,University of Turin | Tomassy G.S.,Harvard University | Morello N.,University of Turin | Calcagno E.,University of Turin | And 2 more authors.
Journal of Neurochemistry | Year: 2014

Rett syndrome (RTT, MIM312750), a neurodevelopmental disorder predominantly occurring in females, is caused in the majority of cases by sporadic mutations in the gene encoding the transcriptional modulator methyl-CpG-binding protein 2 (MECP2). In mice, impaired MeCP2 function results in severe motor, cognitive, and emotional defects. The lack of Mecp2 in γ-aminobutyric acid-(GABA) releasing forebrain interneurons (INs) recapitulate many RTT features, however, the role of this gene in the development of the cortical inhibitory system is still unknown. Here, we found that MeCP2 expression varies among the three major classes of cortical INs and its nuclear localization differs between neuronal types. The density of calretinin+ and parvalbumin+ INs increases in Mecp2 knockout mice (Mecp2-/y) already at early post-natal developmental stages. In contrast, the density of somatostatin+ INs is not affected. We also found that the development of multipolar-calretinin+ INs is selectively affected by the absence of Mecp2. Additionally, we show that in Mecp2 heterozygous female mice, a model closely mimicking human RTT condition, IN abnormalities are similar to those observed in Mecp2-/y mice. Together, our study indicates that loss of function of Mecp2 strongly interferes with the correct establishment of the neocortical inhibitory system producing effects that are specific to different IN subtypes. © 2014 International Society for Neurochemistry.

Zhu L.,University of Turin | Zhu L.,University of Leicester | Sacco T.,University of Turin | Strata P.,University of Turin | And 4 more authors.
PLoS ONE | Year: 2011

Learning to fear dangerous situations requires the participation of basolateral amygdala (BLA). In the present study, we provide evidence that BLA is necessary for the synaptic strengthening occurring during memory formation in the cerebellum in rats. In the cerebellar vermis the parallel fibers (PF) to Purkinje cell (PC) synapse is potentiated one day following fear learning. Pretraining BLA inactivation impaired such a learning-induced long-term potentiation (LTP). Similarly, cerebellar LTP is affected when BLA is blocked shortly, but not 6 h, after training. The latter result shows that the effects of BLA inactivation on cerebellar plasticity, when present, are specifically related to memory processes and not due to an interference with sensory or motor functions. These data indicate that fear memory induces cerebellar LTP provided that a heterosynaptic input coming from BLA sets the proper local conditions. Therefore, in the cerebellum, learninginduced plasticity is a heterosynaptic phenomenon that requires inputs from other regions. Studies employing the electrically-induced LTP in order to clarify the cellular mechanisms of memory should therefore take into account the inputs arriving from other brain sites, considering them as integrative units. Based on previous and the present findings, we proposed that BLA enables learning-related plasticity to be formed in the cerebellum in order to respond appropriately to new stimuli or situations. © 2011 Zhu et al.

Zorzan S.,University of Verona | Lorenzetto E.,University of Verona | Ettorre M.,University of Verona | Pontelli V.,University of Verona | And 3 more authors.
Bioinformatics | Year: 2013

Motivation: Comparative studies are encouraged by the fast increase of data availability from the latest high-throughput techniques, in particular from functional genomic studies. Yet, the size of datasets, the challenge of complete orthologs findings and not last, the variety of identification formats, make information integration challenging. With HOMECAT, we aim to facilitate cross-species relationship identification and data mapping, by combining orthology predictions from several publicly available sources, a convenient interface for high-throughput data download and automatic identifier conversion into a Cytoscape plug-in, that provides both an integration with a large set of bioinformatics tools, as well as a user-friendly interface. © 2012 The Author.

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